Preparation of aqueous clear solution dosage forms with bile acids

• US 6,251,428 B1
• Filed: 07/20/1999
• Issued: 06/26/2001
• Est. Priority Date: 07/24/1998
• Status: Expired due to Fees

• Current Assignee: Seo Hong Yoo
• Original Assignee: Seo Hong Yoo
• Inventors: Yoo, Seo Hong
• Primary Examiner(s): Cintins, Marianne M.
• Assistant Examiner(s): KIM, VICKIE Y
• Application Number:
  US09/357,549
• Time in Patent Office: 707 Days
• Field of Search: 424/455, 424/456, 424/479
• US Class Current: 424/455
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/06 Antihyperlipidemics

Abstract

Compositions for pharmaceutical and other uses for preparing clear aqueous solutions containing bile acids which do not form precipitates over selected ranges of pH values of the aqueous solution and methods of making such solutions. The compositions of the invention comprise water; a bile acid in the form of a bile acid, bile acid salt, or a bile acid conjugated with an amine by an amide linkage; and a high molecular weight aqueous soluble starch conversion product. The composition remains in solution without forming a precipitate over a range of pH values and, according to one embodiment, remains in solution for all pH values obtainable in an aqueous system. The composition, according to some embodiments, may further contain a pharmaceutical compound in a pharmaceutically effective amount.

Claims

1. An clear aqueous solution comprising:

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a second material selected from the group consisting of dextran and liquid glucose; and

(c) water,

wherein the first and second materials both remain in solution for all pH values of the solution within a selected range of pH values and wherein the weight ratio of the second material to the first material is less than about 30;

1.

4. The aqueous solution of any one of claims 1, 2 or 3 wherein the first material is present in a pharmaceutically effective amount.

5. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution additionally comprises a pharmaceutically effective amount of a pharmaceutical compound and the pharmaceutical compound remains in solution for all pH values within the selected range.

6. The aqueous solution of claim 5 wherein the pharmaceutical compound is selected from the group consisting of insulin, heparin, calcitonin, ampicillin, amantadine, rimantadine, sildenafil, apomorphine, yohimbin, trazodone, ribavirin, neomycin sulfate, paclitaxel and its derivatives, retinol and tretinoin.

7. The aqueous solution of claim 5 wherein the first material is ursodeoxycholic acid and the pharmaceutical compound is selected from the group consisting of metformin HCl, ranitidine HCl, cimetidine, lamivudine, cetrizine 2HCl, amantadine, rimantadine, sildenafil, apomorphine, yohimbine, trazodone, ribavirin, dexamethasone, hydrocortisone, prednisolone, triamcinolone, cortisone, niacin, catechin and its derivatives, taurine, vitamins, and naturally occurring amino acids.

8. The aqueous solution of any one of claims 1, 2 or 3 wherein the selected pH range is between approximately 1 and approximately 10 inclusive.

9. The aqueous solution of anM one of claims 1, 2 or 3 wherein the selected pH range is the range spanned by the prevailing pH values found in the mouth, stomach, and intestines of a mammal.

10. The aqueous solution of any one of claims 1, 2 or 3 wherein the selected pH range is the range spanned by the prevailing pH values found in the mouth, stomach, and intestines of a human being.

11. The aqueous solution of any one of claims 1, 2 or 3 wherein the selected pH range is a range of pH values obtainable in an aqueous system encountered by the solution duiing preparation, administration and until absorption in the body to which the solution is administered.

12. The aqueous solution of any one of claims 1, 2 or 3 wherein the selected pH range spans all obtainable pH values in an aqueous system.

13. The aqueous solution of any one of claims 1, 2 or 3 wherein the first material is selected from the group consisting of ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodeoxycholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, their derivatives at a hydroxyl or carboxylic acid group on the steroid nucleus, their salts, or their conjugates with amines.

14. The aqueous solution of anM one of claims 1 or 2 wherein the bile acid salt is a product of the reaction of a bile acid and an amine.

15. The aqueous solution of claim 14 wherein the bile acid is selected from the group consisting of ursodexycholic acid, chenodeoxycholic acid, cholic acid, hyodeoxycholic acid, deoxycholic acid, 7-oxolithocholic acid, iododeoxycholic acid, iocholic acid, tauroursodexycholic acid, glycocholic acid, and their derivates at a hydroxyl or carboxylic acid group on the steroid nucleus.

16. The aqueous solution of claim 14 wherein the amine is selected from the group consisting of an aliphatic free amine, trintine, dietylene triamine, tetraethylene pentamine, a basic amino acid, arginine, lysine, lysine, ornithine, ammonia, an amino sugar, D-glucamine, N-alkylglucamines, a quaternary ammonium derivative, choline, an heterocyclic amine, piperazine, N-alkylpiperazine, piperidine, N-alkylpiperidine, morpholine, N-alkylmorphline, pyrrolidine, triethanolamnine, and trimethanolaminie.

17. The aqueous solution of any one of claims 1, 2 or 3 wherein the bile acid salt is a soluble metal salt of a bile acid or an aqueous soluble O-sulfonated bile acid.

18. The aqueous solution of anM one of claims 1, 2 or 3 wherein the second material is the product of partial or incomplete hydrolysis of a starch.

19. The aqueous solution of claim 18 wherein the starch is selected from the group consisting of maltodextri, dextrin, dextran, liquid glucose, and soluble starch.

20. The aqueous solution of claim 5 wherein the first material is an adjuvant.

21. The aqueous solution of claim 5 wherein the first material is a carrier of the pharmaceutical compound.

22. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution further comprises a micelle forming material.

23. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a preparation for oral consumption.

24. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in an enema.

25. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a mouthwash.

26. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a gargle.

27. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a preparation for nasal administration.

28. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a preparation for otic administration.

29. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in an injection.

30. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a douche.

31. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a topical skin preparation.

32. The aqueous solution of any one of claims 1, 2 or 3 wherein the solution is comprised in a cosmetic preparation.

2. An clear aqueous solution comprising:

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a second material selected from the group consisting of dextran and liquid glucose; and

(c) water,

wherein the first and second materials both remain in solution for all pH values of the solution within a selected range of pH values and wherein the concentration of the first material is more than about 1.17% (W/W).

3. An clear aqueous solution comprising:

(a) a first material selected from the group consisting of a bile acid, an aqueous soluble derivative of a bile acid, a bile acid salt, and a bile acid conjugated with an amine by an amide linkage;

(b) a second material selected from the group consisting of dextran and liquid glucose; and

(c) water,

wherein the first and second materials both remain in solution for all pH values of the solution within a selected range of pH values and wherein the concentration of the second material is more than about 35% (W/W).

33. A method of preparing an aqueous solution wherein the solution forms no precipitate at any pH value of the solution within a selected range of pH values comprising:

(a) dissolving a bile acid, bile acid salt, or bile acid-amine conjugate in water to form a clear solution;

(b) adding an aqueous soluble starch conversion product to the clear solution and allowing it to dissolve to form a clear solution; and

(c) optionally adding a pharmaceutically effective amount of a pharmaceutical compound.

34. The method of claim 33 wherein the selected range is all pH values obtainable in an aqueous system.

35. The method of claim 33 wherein the selected range is between approximately pH 1 and approximately pH 10.